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Tigecycline

TIGECYCLINE

Tigecycline is an injectable glycylcycline antibacterial product.

Tigecyclines are semi synthetic derivatives of tetracycline antibiotics with a glycylamido moiety attached at the 9 position of the D-ring of the base molecule. This modification maintains the antibacterial effect but provides stability against mechanisms of tetracycline resistance.

 

Mechanism of action:

Tigecycline inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. In general, tigecycline is considered bacteriostatic.

TYGACIL binds to the ribosome, thereby inhibiting protein synthesis

 

Glycylcyclines overcome key mechanisms of resistance

  • Glycylcyclines — which include TYGACIL — bind to the ribosome with five times higher affinity than tetracycline
  • TYGACIL binds to additional sites of the ribosome in a manner not seen before, interfering with the mechanism of ribosomal protection proteins
  • TYGACIL is not expelled by macrolide or tetracycline efflux pumps

TYGACIL provides an expanded broad spectrum of in vitro activity

  • Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), and vancomycin-resistant enterococci (VRE)—Enterococcus faecalis and Enterococcus faecium1
  • Gram-negative pathogens, including Acinetobacter baumannii and Stenotrophomonas maltophilia
  • Anaerobic pathogens

 

Tigecycline is generally considered bacteriostatic.

Pharmacokinetic studies of tigecycline have been conducted in healthy subjects and in special patient populations such as those with hepatic or renal impairment and the elderly. In studies involving healthy subjects given intravenous (IV) tigecycline (100 mg followed by 50 mg every 12 hours), the steady-state Cmax was 0.87 ± 0.23 μg/mL for 30-minute infusions and 0.63 ± 0.097 μg/mL for 60-minute infusions; the steady-state AUC0-12h was 2.35 ± 0.85 μg•h/mL. The graph below presents the serum concentration-time profile in a typical subject.

Serum Concentration-Time Profile

 

Protein Binding

The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 μg/mL). The moderate degree of protein binding observed in vitro is unlikely to result in drug-drug interactions that would significantly impact the safety or efficacy of tigecycline.

Distribution

The steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating that tigecycline is extensively distributed beyond the plasma volume and into the tissues.

Metabolism

Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers receiving 14C-tigecycline, tigecycline was the primary 14C-labeled material recovered in urine and feces, but a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.

Elimination

Following IV administration, tigecycline serum concentrations initially decline rapidly during distribution into body tissues. The mean half-life of tigecycline after a single 100-mg dose was 27.1 hours; after multiple dosing of 50 mg every 12 hours, the mean half-life was 42.4 hours. Approximately 59% of a radioactive dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Of the total dose, approximately 22% is excreted as unchanged tigecycline in urine. The majority of the urine recovery (22%) occurred on the first day. Conversely, very little fecal recovery occurred on day 1 (0.03%), with the majority recovered thereafter. The primary route of elimination of tigecycline is biliary excretion of unchanged tigecycline and its metabolites. Secondary routes are renal excretion of unchanged tigecycline, glucuronidation, and amide hydrolysis followed by N-acetylation to form N-acetyl-9-aminominocycline.

Postantibiotic Effect

The in vitro postantibiotic effect of tigecycline was 3.4 to 4 hours for strains of S. aureus and 1.8 to 2.9 hours for strains of E. coli, including those carrying selected resistance determinants. In a localized neutropenic mouse thigh infection model, tigecycline exhibited a long in vivo postantibiotic effect: 8.9 hours for S. pneumoniae and 4.9 hours for E. coli. Both area under the curve (AUC) and time above a fraction of minimum inhibitory concentration (MIC) correlated with efficacy. Because tigecycline exhibited time-dependent bacterial killing properties in combination with a moderate-to-prolonged postantibiotic effect, the AUC/MIC ratio is likely the primary pharmacokinetic/pharmacodynamic determinant of efficacy.

 

Indications and Usage

TYGACIL is indicated for the treatment of adults with:

  • complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus group (includes anginosus, S. intermedius, and
    S. constellatus), Streptococcus pyogenes, and Bacteroides fragilis

complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus anginosus group (includes
S. anginosus
, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron,
Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros

 

 

TYGACIL recommended dosage regimen:

  • 100 mg initial dose
  • 50 mg every 12 hours
  • In severe hepatic impairment, the initial dose should be 100 mg followed by a reduced dose of 25 mg every 12 hours
  • Intravenous infusions should be administered over approximately 30 to 60 minutes every 12 hours Incompatibilities:
  • Amphotericin B and Diazepam should not be administered simultaneously .

Important Safety Information

  • To reduce the development of drug-resistant bacteria and maintain the effectiveness of TYGACIL and other antibacterial drugs, TYGACIL should be used only to treat infections proven or strongly suspected to be caused by susceptible bacteria
  • Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening
  • TYGACIL is contraindicated in patients with known hypersensitivity to tigecycline
  • TYGACIL should be administered with caution in patients with known hypersensitivity to tetracycline class antibiotics
  • Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACIL
  • In clinical trials, the most common treatment-emergent adverse events in patients treated with TYGACIL were nausea (29.5%) and vomiting (19.7%)
  • TYGACIL may cause fetal harm when administered to a pregnant woman
  • The safety and effectiveness of TYGACIL in patients below age 18 and lactating women have not been established
  • Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal colitis
  • Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective
  • The use of TYGACIL during tooth development may cause permanent discoloration of the teeth. TYGACIL should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated
  • Prothrombin time or other suitable anticoagulant test should be monitored if TYGACIL is administered with warfarin
  • Monotherapy should be used with caution in patients with clinically apparent intestinal perforation
  • In patients with severe hepatic impairment (Child Pugh C), the initial dose of TYGACIL should be 100 mg followed by 25 mg every 12 hours. Patients should be treated with caution and monitored for treatment response
  • The following drugs should not be administered simultaneously through the same Y-site as TYGACIL: amphotericin B and diazepam

 

REFERENCES:

  • Testa RT, Petersen PJ, Jacobus NV, et al. In vitro and in vivo antibacterial activities of the glycylcyclines, a new class of semisynthetic tetracyclines. Antimicrob Agents Chemother. 1993;37:2270-2277.
  • Garrison MW, Neumiller JJ, Setter SM. Tigecycline: an investigational glycylcycline antimicrobial with activity against resistant gram-positive organisms. Clin Ther. 2005;27:12-22.
  • Bergeron J, Ammirati M, Danley D, et al. Glycylcyclines bind to the high-affinity tetracycline ribosomal binding site and evade Tet(M)- and Tet(O)-mediated ribosomal protection. Antimicrob Agents Chemother. 1996;40:2226-2228.
  • Bauer G, Berens C, Projan SJ, et al. Comparison of tetracycline and tigecycline binding to ribosomes mapped by dimethylsulphate and drug-directed Fe2+ cleavage of 16S rRNA. J Antimicrob Chemother. 2004;53:592-599.
  • Bradford PA. Tigecycline: a first in class glycylcycline. Clinical Microbiology Newsletter. 2004;26:163-168.
  • Data on file, Wyeth Pharmaceuticals Inc.
  • Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections; results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis. 2005:41(suppl 5):S341-S353.
  • Babinchak T, Ellis-Grosse EJ, Dartois N, et al. The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis. 2005;41(suppl 5):S354-S367.
  • Waites KB, Duffy LB, Dowzicky MJ. Antimicrobial susceptibility among pathogens collected from hospitalized patients in the United States and in vitro activity of tigecycline, a new glycylcycline antimicrobial. Antimicrob Agents Chemother. 2006;50:3479-3484.
  • Hoban DJ, Bouchillon SK, Johnson BM, et al. In vitro activity of tigecycline against 6792 gram-negative and gram-positive clinical isolates from the global Tigecycline Evaluation and Surveillance Trial (TEST program, 2004). Diagn Microbiol Infect Dis. 2005;52:215-227.
  • E.S.T. Web site. http://www.testsurveillance.com